Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Validation of the Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) quality assessment tool.

BACKGROUND: The Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) was developed to undertake streamlined quality audits of antifungal prescribing. The validity and reliability of such tools is not characterized. OBJECTIVES: To assess the validity and reliability of the AF-NAPS quality assessment tool. METHODS: Case vignettes describing antifungal prescribing were prepared. A steering group was assembled to determine gold-standard classifications for appropriateness and guideline compliance. Infectious diseases physicians, antimicrobial stewardship (AMS) and specialist pharmacists undertook a survey to classify appropriateness and guideline compliance of prescriptions utilizing the AF-NAPS tool. Validity was measured as accuracy, sensitivity and specificity compared with gold standard. Inter-rater reliability was measured using Fleiss' kappa statistics. Assessors' responses and comments were thematically analysed to determine reasons for incorrect classification. RESULTS: Twenty-eight clinicians assessed 59 antifungal prescriptions. Overall accuracy of appropriateness assessment was 77.0% (sensitivity 85.3%, specificity 68.0%). Highest accuracy was seen amongst specialist (81%) and AMS pharmacists (79%). Prescriptions with lowest accuracy were in the haematology setting (69%), use of echinocandins (73%), mould-active azoles (75%) and for prophylaxis (71%). Inter-rater reliability was fair overall (0.3906), with moderate reliability amongst specialist pharmacists (0.5304). Barriers to accurate classification were incorrect use of the appropriateness matrix, knowledge gaps and lack of guidelines for some indications. CONCLUSIONS: The AF-NAPS is a valid tool, assisting assessors to correctly classify appropriate prescriptions more accurately than inappropriate prescriptions. Specialist and AMS pharmacists had similar performance, providing confidence that both can undertake AF-NAPS audits to a high standard. Identified reasons for incorrect classification will be targeted in the online tool and educational materials.

Planned combined onco-plastic (COP) surgical approach improves oncologic outcomes in soft tissue sarcomas.

BACKGROUND: Combined modality of radiotherapy and surgery is the standard of treatment of soft tissue sarcomas (STS). The goal of this study was to assess whether a Combined Onco-Plastic (COP) surgical approach in the setting of neo-adjuvant radiotherapy can improve the oncologic outcomes of STS and reduce the rate of wound complications. METHODS: We performed a retrospective review of all patients with STS treated at a single sarcoma centre (St Vincent's Hospital, Melbourne) between 2007 and 2018. Patients were stratified into two groups based on whether they have received the COP approach or were closed primarily by the orthopaedic surgeon. We analysed oncological outcomes and rate of wound complications. RESULTS: A total of 546 patients with comparable demographics and tumor characteristics were included. The COP approach was performed in 75.6% of the patients. Wide margins were obtained in 97.4% of the cases, and this was significantly higher in the COP group (p < 0.001). The cumulative rate of local recurrence was 4.9%, with a 52% risk reduction in the COP approach, although this reduction was not significant (HR = 0.48; 95% CI 0.21-1.06; p = 0.070). The COP approach had better disease free survival (DFS) (aHR 1.86, 95% CI 1.45-2.37; p < 0.001) and Overall survival (risk of death aHR 0.49; 95% CI 0.30-0.79; p = 0.004). The overall wound complication rate was 18.6% with no difference between the two groups. CONCLUSION: A planned collaboration between the orthopaedic oncologist and the plastic surgeon is beneficial in the treatment of STS after neo-adjuvant radiotherapy, allowing remarkably good oncological outcomes and a low rate of wound complications.

Shock wave propagation along the central retinal blood vessels.

Retinal haemorrhage is often observed following brain injury. The retinal circulation is supplied (drained) by the central retinal artery (vein) which enters (leaves) the eye through the optic nerve at the optic disc; these vessels penetrate the nerve immediately after passing through a region of cerebrospinal fluid (CSF). We consider a theoretical model for the blood flow in the central retinal vessels, treating each as multi-region collapsible tubes, where we examine how a sudden change in CSF pressure (mimicking an injury) drives a large amplitude pressure perturbation towards the eye. In some cases, this wave can steepen to form a shock. We show that the region immediately proximal to the eye (within the optic nerve where the vessels are strongly confined by the nerve fibres) can significantly reduce the amplitude of the pressure wave transmitted into the eye. When the length of this region is consistent with clinical measurements, the CSF pressure perturbation generates a wave of significantly lower amplitude than the input, protecting the eye from damage. We construct an analytical framework to explain this observation, showing that repeated rapid propagation and reflection of waves along the confined section of the vessel distributes the perturbation over a longer lengthscale.

The prognostic significance of attenuated psychotic symptoms in help-seeking youth.

BACKGROUND: Recent findings suggest that attenuated psychotic symptoms (APS) might serve as a risk factor for general mental health impairment in help-seeking youth. The current study was designed to test this possibility by examining the prognostic significance of APS in a large cohort of help-seeking youth not selected for psychosis risk. METHOD: 465 youth aged 12-25 referred to general youth mental health services were grouped as either APS + or APS- based on whether or not they met 'ultra high risk' for psychosis APS risk criteria as assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS). They completed clinical assessments at baseline and at 12-month follow-up, measuring a range of psychopathology (depression, anxiety, eating disorders, general psychological distress, substance abuse) and psychosocial functioning. RESULTS: APS + had significantly poorer outcomes at 12-months on a range of clinical variables, even after adjusting for baseline scores and amount of treatment received. However, the APS + group showed greater improvement in functioning at follow-up compared to APS-. CONCLUSION: Attenuated psychotic symptoms are a prognostic indicator of persistent transdiagnostic mental health problems and reduced response to treatment in help-seeking youth over the short term. Hence, it is critical to screen and assess attenuated psychotic symptoms at the primary and secondary mental health services level, especially given that these subclinical symptoms are rarely voluntarily reported.

The impact of older age on patient outcomes following primary total knee arthroplasty.

AIMS: As the population ages, there is projected to be an increase in the level of demand for total knee arthroplasty (TKA) in octogenarians. We aimed to explore whether those aged ≥ 80 years achieved similar improvements in physical function to younger patients while also comparing the rates of length of stay (LOS), discharge to rehabilitation, postoperative complications, and mortality following TKA in older and younger patients. PATIENTS AND METHODS: Patients from one institution who underwent primary elective TKA between 1 January 2006 and 31 December 2014 were dichotomized into those ≥ 80 years old (n = 359) and those < 80 years old (n = 2479) for comparison. Multivariable regression was used to compare the physical status component of the 12-Item Short-Form Health Survey (SF-12), LOS, discharge to rehabilitation, complications, and mortality between the two groups. RESULTS: Both age groups demonstrated a clinically meaningful improvement in their self-reported physical health relative to their baseline with no clinically relevant difference noted between them. Being ≥ 80 years old was associated with a 0.58-day increase in LOS and older patients were more likely to be discharged to rehabilitation (odds ratio (OR) 3.06, p < 0.001). Medical complications and mortality were higher in elderly patients (OR 1.92 for complications, p < 0.001; hazard ratio 3.40 for death, p < 0.001). There was no statistically significant association between age group and experiencing a postoperative surgical or wound-related complication. CONCLUSION: Those aged over 80 years achieved a statistically significant lower median SF-12 physical score than the younger group, after adjusting for the preoperative score, but this difference of 4.46 was not considered to be clinically meaningful. However, clinicians should be aware that the elderly are at a higher risk of experiencing longer hospital stays, postoperative medical complications, and mortality. Cite this article: Bone Joint J 2018;100-B:1463-70.

Central and peripheral line-associated bloodstream infections in Australian neonatal and paediatric intensive care units: findings from a comprehensive Victorian surveillance network, 2008-2016.

BACKGROUND: Healthcare-associated infections in neonatal and paediatric populations are associated with poorer outcomes and healthcare costs, and surveillance is a necessary component of prevention programmes. AIM: To evaluate burden of illness, aetiology, and time-trends for central and peripheral line-associated bloodstream infection (CLABSI and PLABSI) in Australian neonatal and paediatric intensive care units (ICUs) between July 1st, 2008 and December 31st, 2016. METHODS: Using National Healthcare Safety Network methods, surveillance in neonatal and paediatric units was performed by hospitals participating in the Victorian Healthcare Associated Infection Surveillance System. Mixed effects Poisson regression was used to model infections over time. FINDINGS: Overall, 82 paediatric CLABSI events were reported during 37,125 CVC-days (2.21 per 1000 CVC-days), 203 neonatal CLABSI events were reported during 92,169 CVC-days (2.20 per 1000 CVC-days), and 95 neonatal PLABSI events were reported during 142,240 peripheral line-days (0.67 per 1000 peripheral line-days). Over time, a significant decrease in quarterly risk for neonatal CLABSI events was observed (risk ratio (RR): 0.98; 95% confidence interval: 0.97-0.99; P = 0.023) and this reduction was significant for the 751-1000 g birth weight cohort (RR: 0.97; P = 0.015). Most frequently, coagulase-negative Staphylococcus spp. (24.2%) and Staphylococcus aureus (16.1%) were responsible for CLABSI events. A significant reduction in Gram-negative neonatal infections was observed (annual RR: 0.85; P < 0.001). CONCLUSION: CLABSI rates in neonatal and paediatric ICUs in our region are low, and neonatal infections have significantly diminished over time. Evaluation of infection prevention programmes is required to determine whether specific strategies can be implemented to further reduce infection risk.

Three-dimensional knee kinematic analysis during treadmill gait: Slow imposed speed versus normal self-selected speed.

OBJECTIVES: Whilst gait speed is variable between healthy and injured adults, the extent to which speed alone alters the 3D in vivo knee kinematics has not been fully described. The purpose of this prospective study was to understand better the spatiotemporal and 3D knee kinematic changes induced by slow compared with normal self-selected walking speeds within young healthy adults. METHODS: A total of 26 men and 25 women (18 to 35 years old) participated in this study. Participants walked on a treadmill with the KneeKG system at a slow imposed speed (2 km/hr) for three trials, then at a self-selected comfortable walking speed for another three trials. Paired t-tests, Wilcoxon signed-rank tests, Mann-Whitney U tests and Spearman's rank correlation coefficients were conducted using Stata/IC 14 to compare kinematics of slow versus self-selected walking speed. RESULTS: Both cadence and step length were reduced during slow gait compared with normal gait. Slow walking reduced flexion during standing (10.6° compared with 13.7°; p < 0.0001), and flexion range of movement (ROM) (53.1° compared with 57.3°; p < 0.0001). Slow walking also induced less adduction ROM (8.3° compared with 10.0°; p < 0.0001), rotation ROM (11.4° compared with 13.6°; p < 0.0001), and anteroposterior translation ROM (8.5 mm compared with 10.1 mm; p < 0.0001). CONCLUSION: The reduced spatiotemporal measures, reduced flexion during stance, and knee ROM in all planes induced by slow walking demonstrate a stiff knee gait, similar to that previously demonstrated in osteoarthritis. Further research is required to determine if these characteristics induced in healthy knees by slow walking provide a valid model of osteoarthritic gait.Cite this article: N. Mannering, T. Young, T. Spelman, P. F. Choong. Three-dimensional knee kinematic analysis during treadmill gait: Slow imposed speed versus normal self-selected speed. Bone Joint Res 2017;6:514-521. DOI: 10.1302/2046-3758.68.BJR-2016-0296.R1.

Central line-associated bloodstream infections in Australian ICUs: evaluating modifiable and non-modifiable risks in Victorian healthcare facilities.

Central line-associated bloodstream infections (CLABSIs) in intensive care units (ICUs) result in poor clinical outcomes and increased costs. Although frequently regarded as preventable, infection risk may be influenced by non-modifiable factors. The objectives of this study were to evaluate organisational factors associated with CLABSI in Victorian ICUs to determine the nature and relative contribution of modifiable and non-modifiable risk factors. Data captured by the Australian and New Zealand Intensive Care Society regarding ICU-admitted patients and resources were linked to CLABSI surveillance data collated by the Victorian Healthcare Associated Infection Surveillance System between 1 January 2010 and 31 December 2013. Accepted CLABSI surveillance methods were applied and hospital/patient characteristics were classified as 'modifiable' and 'non-modifiable', enabling longitudinal Poisson regression modelling of CLABSI risk. In total, 26 ICUs were studied. Annual CLABSI rates were 1·72, 1·37, 1·00 and 0·93/1000 CVC days for 2010-2013. Of non-modifiable factors, the number of non-invasively ventilated patients standardised to total ICU bed days was found to be independently associated with infection (RR 1·07; 95% CI 1·01-1·13; P = 0·030). Modelling of modifiable risk factors demonstrated the existence of a policy for mandatory ultrasound guidance for central venous catheter (CVC) localisation (RR 0·51; 95% CI 0·37-0·70; P < 0·001) and increased number of sessional specialist full-time equivalents (RR 0·52; 95% CI 0·29-0·93; P = 0·027) to be independently associated with protection against infection. Modifiable factors associated with reduced CLABSI risk include ultrasound guidance for CVC localisation and increased availability of sessional medical specialists.

Epidemiology of infections and antimicrobial use in Australian haemodialysis outpatients: findings from a Victorian surveillance network, 2008-2015.

BACKGROUND: Patients with chronic renal failure who require haemodialysis are at high risk for infections. AIM: To determine the burden of bloodstream and local access-related infections and the prescribing patterns for intravenous antibiotics in Australian haemodialysis outpatients. METHODS: A surveillance network was established following stakeholder consultation, with voluntary participation by haemodialysis centres and data collation by the Victorian Healthcare Associated Infection Surveillance System Coordinating Centre. Definitions for infection and intravenous antimicrobial starts were based upon methods employed by the Centers for Disease Control and Prevention. Longitudinal mixed-effects Poisson regression was used to model time-trends for the period 2008-2015. FINDINGS: Forty-eight of 78 Victorian dialysis centres participated in the network, with 3449 events reported over 78,826 patient-months. Rates of bloodstream infection, local infection and intravenous antimicrobial starts were much higher for patients with tunnelled central lines (2.60, 1.41, and 3.37 per 100 patient-months, respectively), compared to those with arteriovenous fistulae (0.27, 0.23, and 0.73 per 100 patient-months, respectively) and arteriovenous grafts (0.76, 1.08, 1.50 per 100 patient-months, respectively). Staphylococcus aureus was the most frequent pathogen, with meticillin-resistant isolates (MRSA) responsible for 14.0%. Access-related infections diminished significantly across all vascular-access modalities over time. Vancomycin contributed nearly half of all antimicrobial starts consistently throughout the study period. CONCLUSION: Risk for bloodstream and local access-related infections is highest in Australian haemodialysis patients with tunnelled central lines. S. aureus is the most frequent cause of infection, with a low incidence of MRSA. Future programmes should evaluate infection prevention practices and appropriateness of antibiotic prescribing in this population.

Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis.

Genetic studies have demonstrated association between single-nucleotide polymorphisms within the IL2RA (interleukin-2 receptor α-subunit) gene and risk of developing multiple sclerosis (MS); however, these variants do not have obvious functional consequences. DNA methylation is a source of genetic variation that could impact on autoimmune disease risk. We investigated DNA methylation of the IL2RA promoter in genomic DNA obtained from peripheral blood mononuclear cells and neural tissue using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A differential methylation profile of IL2RA was identified, suggesting that IL2RA expression was regulated by DNA methylation. We extended our analysis of DNA methylation to peripheral blood mononuclear cell (PBMC) of MS cases and controls using MALDI-TOF and Illumina HumanMethylation450 arrays. Analyses of CpG sites within the proximal promoter of IL2RA in PBMC showed no differences between MS cases and controls despite an increase in IL2RA expression. In contrast, we inferred significant DNA methylation differences specific to particular leukocyte subtypes in MS cases compared with controls by deconvolution of the array data. The decrease in methylation in patients correlated with an increase in IL2RA expression in T cells from MS cases in comparison with controls. Our data suggest that differential methylation of the IL2RA promoter in T cells could be an important pathogenic mechanism in MS.

The Epidemiology of Staphylococcus aureus and Panton-Valentine Leucocidin (pvl) in Central Australia, 2006-2010.

BACKGROUND: The Central Australian Indigenous population has a high incidence of Staphylococcus aureus bacteremia (SAB) but little is known about the local molecular epidemiology. METHODS: Prospective observational study of bacteremic and nasal colonizing S.aureus isolates between June 2006 to June 2010. All isolates underwent single nucleotide polymorphism (SNP) genotyping and testing for the presence of the Panton-Valentine Leucocidin (pvl) gene. RESULTS: Invasive isolates (n = 97) were predominantly ST93 (26.6 %) and pvl positive (54.3 %), which was associated with skin and soft tissue infections (OR 4.35, 95 % CI 1.16, 16.31). Non-multiresistant MRSA accounted for 31.9 % of bacteremic samples and showed a trend to being healthcare associated (OR 2.16, 95 % CI 0.86, 5.40). Non-invasive isolates (n = 54) were rarely ST93 (1.9 %) or pvl positive (7.4 %). CONCLUSIONS: In Central Australia, ST93 was the dominant S.aureus clone, and was frequently pvl positive and associated with an aggressive clinical phenotype. Whether non-nasal carriage is more important with invasive clones or whether colonization occurs only transiently remains to be elucidated.

Epidemiology of Clostridium difficile infections in Australia: enhanced surveillance to evaluate time trends and severity of illness in Victoria, 2010-2014.

BACKGROUND: With epidemic strains of Clostridium difficile posing a substantial healthcare burden internationally, there is a need for longitudinal evaluation of Clostridium difficile infection (CDI) events in Australia. AIM: To evaluate time trends and severity of illness for CDI events in Australian healthcare facilities. METHODS: All CDI events in patients admitted to Victorian public hospitals between 1(st) October 2010 and 31(st) December 2014 were reported to the Victorian Healthcare Associated Infection Surveillance System. CDI was defined as the isolation of a toxin-producing C. difficile organism in a diarrhoeal specimen, and classified as community-associated (CA-CDI) or healthcare-associated (HA-CDI). Severe disease was defined as admission to an intensive care unit, requirement for surgery and/or death due to infection. Time trends were examined using a mixed-effects Poisson regression model, and the Walter and Edward test of seasonality was applied to evaluate potential cyclical patterns. FINDINGS: In total, 6736 CDI events were reported across 89 healthcare facilities. Of these, 4826 (71.6%) were HA-CDI, corresponding to a rate of 2.49/10,000 occupied bed days (OBDs). The incidence of HA-CDI was highest in the fifth quarter of surveillance (3.6/10,000 OBDs), followed by a reduction. Severe disease was reported in 1.66% of events, with the proportion being significantly higher for CA-CDI compared with HA-CDI (2.21 vs 1.45%, P = 0.03). The highest and lowest incidence of HA-CDI occurred in March and October, respectively. CONCLUSIONS: A low incidence of HA-CDI was reported in Victoria compared with US/European surveillance reports. Seasonality was evident, together with diminishing HA-CDI rates in 2012-2014. Severe infections were more common in CA-CDI, supporting future enhanced surveillance in community settings.

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

BACKGROUND AND PURPOSE: Early relapse outcomes in long-term stable patients switching from interferon ß/glatiramer acetate (IFNß/GA) to oral therapy are unknown. OBJECTIVE: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNß/GA, relative to a propensity-matched comparator of patients remaining on IFNß/GA. METHODS: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNß/GA ('stayers') using a Cox marginal model. RESULTS: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). CONCLUSION: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

Incidence and predictors of non-fatal drug overdose after release from prison among people who inject drugs in Queensland, Australia.

INTRODUCTION: Release from prison is a period of elevated risk for drug-related harms, particularly among people who inject drugs (PWID). Non-fatal overdose can cause serious morbidity and predicts future fatal overdose, however neither the incidence nor the risk factors for non-fatal overdose following release from prison are well understood. METHODS: Structured health-related interviews were conducted with 1051 adult prisoners in Queensland, Australia prior to release and approximately 1, 3 and 6 months post-release. Incidence of self-reported overdose in the community was calculated for PWID and all prisoners for three discrete time periods. Negative binomial regression with robust error variance was used to identify pre-release predictors of overdose among PWID. RESULTS: The incidence of reported overdose was highest between 1 and 3 months post-release (37.8 per 100 person-years (PY) among PWID; 24.5/100 PY among all ex-prisoners). In adjusted analyses, the risk of post-release non-fatal overdose was higher for PWID who reported: being unemployed for >6 months before prison, having been removed from family as a child, at least weekly use of benzodiazepines and/or pharmaceutical opiates in the 3 months prior to prison, and ever receiving opioid substitution therapy (OST). Pre-release psychological distress and a lifetime history of mental disorder also predicted overdose, whereas risky alcohol use in the year before prison was protective. CONCLUSIONS: PWID have a high risk of overdose following release from prison. Imprisonment is an opportunity to initiate targeted preventive interventions such as OST, overdose prevention training and peer-delivered naloxone for those with a high risk profile.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort.

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.

The occurrence of dystonia in upper-limb multiple sclerosis tremor.

BACKGROUND: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. OBJECTIVE: To investigate whether dystonia contributes to MS tremor and its severity. METHODS: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp. RESULTS: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001). CONCLUSIONS: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction.

A longitudinal study of hepatitis C virus testing and infection status notification on behaviour change in people who inject drugs.

BACKGROUND: Hepatitis C virus (HCV) testing and counselling have the potential to impact individual behaviour and transmission dynamics at the population level. Evidence of the impact of an HCV-positive status notification on injection risk reduction is limited. The objective of our study was to (1) assess drug and alcohol use and injection risk behaviours following notification; (2) to compare behaviour change in people who inject drugs (PWID) who received a positive test result and those who remained negative; and (3) to assess the effect of age on risk behaviour. METHODS: Data from the International Collaboration of Incident HIV and HCV Infection in Injecting Cohorts (InC3 Study) were analysed. Participants who were initially HCV seronegative were followed prospectively with periodic HCV blood testing and post-test disclosure and interview-administered questionnaires assessing drug use and injection behaviours. Multivariable generalised estimating equations were used to assess behavioural changes over time. RESULTS: Notification of an HCV-positive test was independently associated with a small increase in alcohol use relative to notification of a negative test. No significant differences in postnotification injection drug use, receptive sharing of ancillary injecting equipment and syringe borrowing postnotification were observed between diagnosis groups. Younger PWID receiving a positive HCV test notification demonstrated a significant increase in subsequent alcohol use compared with younger HCV negative. CONCLUSIONS: The proportion of PWID reporting alcohol use increased among those receiving an HCV-positive notification, increased the frequency of alcohol use postnotification, while no reduction in injection drug use behaviours was observed between notification groups. These findings underscore the need to develop novel communication strategies during post-test notification to improve their impact on subsequent alcohol use and risk behaviours.

BREMSO: a simple score to predict early the natural course of multiple sclerosis.

BACKGROUND AND PURPOSE: Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. METHODS: An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. RESULTS: Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. CONCLUSIONS: BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.

Impact of vanB vancomycin-resistant enterococcal bacteraemia analysed as a time-varying covariate on length of hospital stay.

The impact of vanB vancomycin-resistant enterococci (VRE) bacteraemia on length of stay (LOS) in hospital, after adjusting for the time-varying nature of enterococcal bacteraemia (variable onset of bacteraemia post-admission), is unknown. Survival analyses (time-varying Cox and competing risks regression) were performed on vanB VRE bacteraemia patients, matched 1:1 with vancomycin-susceptible enterococci bacteraemia patients to determine the factors associated with LOS in these patients. In Cox regression analysis, vanB VRE bacteraemia, intensive-care-unit admission, Charlson co-morbidity index score ⩾4, and an increase in the time to receive appropriate antibiotics were associated with prolonged LOS. Competing risks regression which accounts for the influence of in-patient mortality on the ability to observe the event discharge alive from hospital suggests that, vanB VRE bacteraemia was not significantly associated with prolonged LOS. For the first time, the rate of discharge from hospital in patients with vanB VRE bacteraemia has been quantified.